KR20020063851A - Topical treatment for prevention of ocular infections - Google Patents

Abstract

Oxazolidinone antibiotics in the form of polymerizable suspensions or aqueous compositions, used topically to the eye, are useful for treating or preventing ocular infections. Preferred oxazolidinone antibiotic compositions comprise a compound of formula (IV) and a pharmaceutically acceptable salt thereof.

Description

Topical treatment for preventing eye infections {TOPICAL TREATMENT FOR PREVENTION OF OCULAR INFECTIONS}

The eye is susceptible to bacteria and parasites resulting from both traumatic and nontraumatic events. Infections are noted after eye surgery, in response to which guidance is needed to prevent the development of infections. However, even if there is no invasive trauma at the time of surgery, infection of the eyelids, conjunctival conjunctiva, cornea and other ocular tissues may occur.

Since it is difficult to administer antibiotics to infected tissues, there may be an objection to the treatment of infections in eye tissues and / or this may be a problem. In general, ocular infections are treated by topical, systemic, or topical application of antibiotics. The route of administration depends on the antibiotic selected, location of infection and type of infection.

A simple and direct approach to the topical use of antibiotics externally of the eye has a number of advantages, compared to systemic administration, including the prevention of side effects and the reduced chance of breeding resistant strains of bacteria. However, most of the reasons are that many antibiotics are not suitable for topical use on the eyes.

For example, for efficient local use, antibiotics must be able to penetrate tissues of interest, such as the conjunctival sac and cornea. In addition, the penetration rate should be sufficient to provide an effective amount. Many drugs do not have sufficient penetration into the tissues of the eye, keeping in mind that the outer layer of the eye is very different from the tissues of the gastrointestinal tract. Thus, while certain drugs can be readily absorbed into the intestine and introduced into the supplying blood for systemic administration, even if the same drug at the minimum acceptable therapeutic concentration, the drug-free outer layer of the conjunctiva or cornea It may not be absorbed or penetrated by it. The mechanism of delivery or use of the drug for topical administration and for oral administration are entirely different.

Another concern is that antibiotics can be toxic to the eye. Responses to toxicity include hyperemia, swelling and / or blindness. Since toxicity is a phenomenon that manifests itself with concentration, toxicity is particularly problematic for topical administration. The concentration ratio between tear and eye tissue in topical administration generally ranges from about 1: 500 to 1: 1000 due to the penetrating gradient. Thus, although the drug may be nontoxic at the minimum effective concentration, an increase in concentration with respect to topical administration of 500% to 1000% will, of course, result in a toxic response. In addition, the fact that the drug may be compatible with ocular tissues by oral or systemic administration does not predict or deliver toxic tissues associated with topical administration.

The incompatibility of more potential antibiotics is the utility of topical administration by the patient. Although it is assumed that a sufficiently high concentration of antibiotic can be used to administer an effective amount into a target tissue without causing a toxic response, it can nevertheless cause irritation in use. Irritant reactions include temporary burning of eyes, pain and / or excessive tearing. Due to the increased tearing, many antibiotic compositions are washed away, and regardless of whether or not the effective dose is prevented from being administered, the patient may simply refuse the dosing regimen due to irritation. Because of incompatibility with this dosing regimen, the efficacy of the treatment is reduced or extinguished.

It has been confirmed that some antibiotics fully meet the above requirements for topical administration. Antibiotics that have been reported to be useful for topical ocular administration include fluoroquinolone derivatives such as tobramycin, gentamicin, norfloxacin, opfloxacin and ciprofloxacin, naphthyridine, tetracycline and erythromycin. However, in view of the growing number of resistant strains of bacteria, it would be desirable to find additional antibiotics that can be used topically to the eye. It would also be desirable to provide an effective ophthalmic topical formulation for Gram negative aerobic bacteria as well as Gram negative anaerobic organisms.

The present invention relates to a method for treating an eye comprising topically using an oxazolidinone antibiotic in the eye to treat or prevent infection in eye tissue in an effective amount. Applicants have found that oxazolidinone antibiotics belonging to the known group of ocular antibiotics are suitable for topical administration to the eye. Preferred oxazolidinone antibiotics are phenyloxazolidinone, more preferably oxazine or thiazine phenyloxazolidinone.

The present invention also relates to an ophthalmic topical composition containing an oxazolidinone antibiotic. In one embodiment, the ophthalmic composition is a sustained release composition consisting of an aqueous suspension of an oxazolidinone antibiotic and a polymerizable suspending agent.

The present invention includes and provides an aqueous polymerizable suspension comprising water, 0.05% to 5.0% oxazolidinone antibiotic, and 0.1% to 10% polymerizable suspending agent, wherein the polymerizable suspending agent is provided herein. Water swellable and water insoluble crosslinked carboxyl-vinyl polymers.

The present invention includes and provides a composition comprising water, a polymerizable suspending agent and a compound of formula (IV).

The present invention includes and provides a composition comprising water, oxyzolidinone, a polymerizable suspending agent, and a solubility enhancer.

The present invention relates to methods of treating or preventing ocular infections and compositions useful for such uses.

As used herein, "oxazolidinone antibiotic" means a compound having an oxazolidinone nucleus that exhibits antimicrobial activity. Local compound nuclei are substituted as indicated in the segments of the structure:

As known in the art of oxazolidinone antibiotics, the phenyl ring may be substituted by a variety of groups, which may form a ring bonded together with a substituent and / or the oxazolidinone ring itself. The carbonyl moiety is bonded to one of a number of known end groups. By "phenyloxazolidinone" is meant an oxazolidinone ring with a phenyl group bonded to the ring nitrogen as indicated in the above segment, with or without an amidemethylene substituent.

More specifically, the oxazolidinone antibiotics used in the present invention and pharmaceutically acceptable salts thereof can generally be represented by the following formulas (I) and (II):

Where

R ¹ represents (1) -H, (2) NH ₃ , (3) C ₁ -C ₈ alkylamine, (4) C ₁ -C ₈ dialkylamine, (5) C ₁ -C ₈ alkoxy, ( 6) C ₁ -C ₁₂ alkyl optionally substituted with 1-3 Cl, (7) C ₃ -C ₁₂ cycloalkyl, (8) C ₅ -C ₁₂ alkenyl containing one double bond, (9) C ₁ -C ₈ acyloxy, (10) O-CH ² -phenyl, (11) 1-3-OH, -OCH ₃ , -OC ₂ H ₅ , -NO ₂ , -F, -Cl, -Br, Phenyl optionally substituted with —COOH and SO ₃ H, —N (R ^1-1 ) (R ^1-2 ), wherein R ^1-1 and R ^1-2 are the same or different, and they are —H, C ₁ -C ₅ alkyl), (12) furanyl, (13) tetrahydrofuranyl, (14) 2-thiophene, (15) pyrrolidinyl, (16) pyridinyl, (17) -OR ^{1 -3} (wherein R ^1-3 is C ₁ -C ₄ alkyl), (18) -NH ₂ , (19) -NHR ^1-4 , wherein R ^1-4 is C ₁ -C ₃ alkyl Or phenyl), (20) -NR ^1-4 R ^1-5 , wherein R ^1-5 is C ₁ -C ₃ alkyl, R ^1-4 is as defined above, R ^1-4 and R ^1-5 are combined with a nitrogen atom, an oxygen-containing, saturated mono- quality C ₅ -C ₇ may form a heterocyclic _{ring), (21) CH 2 -OH} , and (22) CH ₂ -OR ^1-6 (here, R ^1-6 is C ₁ -C ₄ alkyl Or CO-R ^1-7 is C ₁ -C ₄ alkyl or C ₁ -C ₈ phenyl);

◆ R ² and R ⁴ are the same or different and they are (1) H, (2) -OH, (3) halogen, (4) CF ₃ , (5) OCH ₃ and (6) O-CO-R ^{2 -1} , wherein R ^2-1 is C ₁ -C ₃ alkyl or C ₁ -C ₈ phenyl, provided that only one of R ² or R ⁴ is -H;

◆ R³Silver (1) H, (2) halogen, (3) -O-CH₃, (4) -O-C₂H₅, (5) piperidine, (6) 4-hydroxypyridine, (7) Q [wherein Q is H, -C_One-C₄Alkyl, -NO₂, -NH₂, -MH-CO- [C_One-C₄Alkyl], -CN, -COOH, -O- [C_One-C₄Alkyl], halogen, and N-oxides thereof, substituted or unsubstituted with a substituent selected from the group consisting of:^*H = CH-CH = Z-Y²= W^*(From here,^*Symbols or atoms representing atoms represented by are combined with each other to form a ring, Z, Y²And one of W is -N = and the other is C =); a 5, 6, 7 or 8 membered heterocyclic ring; Q is hydrogen, methyl, ethyl, isopropyl, t-butyl, benzyl, phenyl, pyridyl, acetyl, difluoroacetyl, hydroxyacetyl, benzoyl, methoxy carbonyl, ethoxy carbonyl, 2-chloroethoxy Carbonyl, 2-hydroxyethoxy carbonyl, 2-benzyloxyethyloxy carbonyl, 2-methoxyethoxy carbonyl, 2,2,2-trifluoroethoxy carbonyl, cyanomethyl, 2- Cyanoethyl, carbomethoxymethyl, 2-carbomethoxyethyl, 2-fluoroethoxy carbonyl, benzyloxy carbonyl, t-butoxy carbonyl, methyl sulfonyl, phenyl sulfonyl, or paratoluenesulfonyl C unsubstituted or substituted with a substituent selected from the group consisting of_One-C₄Alkyl; or (8) phenyl, (9) pyridyl, (10) pyrazidyl, (11) pyridazinyl, (12) pyrimidinyl, (13) 1,2 , 3-triazinyl, (14) 1,2,4-triazinyl, (15) 1,2,5-triazinyl, (16) quinolinyl, (17) isoquinolinyl, (18) quinoxali Neil, (19) quinazolinyl, (20) phthalazinyl, (21) shinolinyl, (22) naphthylpyridinyl, (23) R^31-1Indolyl, optionally substituted with nitrogen, (24) R^31-1Pyrrolypyridinyl, (25) furanopyridinyl, (26) thienopyridinyl, (27) benzothiazolyl, (28) benzooxazolyl, with (29) R^31-1Imidazolyl with saturated nitrogen, substituted by (30) R^31-1Pyrazolyl with saturated nitrogen substituted with (31) thiazolyl, (32) isothiazolyl, (33) oxazolyl, (34) isoxazolyl, (35) R^31-1Pyrrolyl having nitrogen substituted with (36) furanyl, (37) thiophenyl optionally substituted with U and V, (37) 1,2,3-triazolyl, (39) R^31-1Where R^31-1Is H, C unsubstituted or substituted with one or more halogens_One-C₄Alkyl, C₃-C₆Cycloalkyl or C (O) R^31-2, In this case R^31-2Is -H, C unsubstituted or substituted with one or more halogens_One-C₄1,2,4-triazolyl with saturated nitrogen substituted with alkyl, or phenyl unsubstituted or substituted with one or more halogens, and 1,2,3-triazolyl and 1,2 , 4-triazolyl is unsubstituted or substituted with U, and in each case of V is H, halogen, R^3-1, OR^3-1Independently selected from a substituent selected from the group consisting of^3-1Is -H, or C_One-C₄Alkyl or NO₂In each case U is (1) H, (2) halogen, -OH, = O, S (O)_nR^3-2[Where R^3-2C_One-C₄Alkyl or C₃-C₈Cycloalkyl and NR^3-3R^3-4, In this case R^3-3And R^3-4Are the same or different and they are H, C_One-C₈Alkyl, C₃-C₈Cycloalkyl, and (CH₂)_rCHOR^3-5, And (CH₂)_rNR^3-6R^3-7R is selected from the group consisting of^3-3And R^3-4Together (CH₂) O (CH₂), (CH₂)_tCH (CO) R^3-8And (CH₂) N (R^3-8) (CH₂)₂Is selected from the group consisting of R in this case^3-5Is H, or C_One-C₄Alkyl or R^3-6And R^3-7Are the same or different, these are H, or C_One-C₄Alkyl or both (CH₂)_rC unsubstituted or substituted with one or more substituents selected from the group consisting of_One-C₈Alkyl, (3) C₂-C₅Alkenyl, (4) C₃-C₈Cycloalkyl, (5) OR^3-3Where R^3-3Is as described above), (6) -CN, (7) S- (O)_n-R^3-8[Where R^3-8Silver halogen, OH, CN, NR^3-3R^3-4Where R^3-3And R^3-4Is as defined above) And CO₂R^3-5Where R^3-5Is as defined above, which is C₂-C₄Alkenyl, NR^3-9R^3-10, In this case R^3-9H, C_One-C₄Alkyl, or C₃-C₈Cycloalkyl, R^3-10Is -H, C_One-C₄Alkyl, C_One-C₄Alkenyl, C₃-C₄Cycloalkyl, -OR^3-5Or NR^3-6R^3-7, N₃, NHC (O) R^3-11, In this case R^3-5, R^3-6And R^3-7Is as defined above and R is^3-11Is C optionally substituted with one or more halogens_One-C₄C unsubstituted or substituted with one or more substituents selected from the group consisting of_One-C₄Alkyl], (8) -S (O)₂-N = S (O)_iR^3-14R^3-15[Where R^3-14And R^3-15Are the same or different and they are C_One-C₂Alkyl or both (CH₂)_q-9], (9) -S-C (O) -R^3-11[Where R^3-11Is as defined above], (10) tetrazole, (11) NR^3-3R^3-4[Where R^3-3And R^3-4Is as defined above], (12) N (R^3-3COR^3-11[Where R^3-3And R^3-11Is as defined above], (13) -N (R^3-3) -S- (O)_nR^3-11[Where R^3-3And R^3-11Is as defined above], (14) -CONR^3-3R^3-4[Where R^3-3And R^3-4Is as defined above], (15) -C (O) R^3-16[Where R^3-16Is -H, -OR^3-5, -OC (O) R^3-5, NR^3-3R^3-4, S (O)_nR^3-17C optionally substituted with_One-C₈Alkyl, C₃-C₈Cycloalkyl, or -CHO or -CO₂R^3-5C optionally substituted with₂-C₅Alkenyl, where R^3-3, R^3-4And R^3-5Is as defined above and R is^3-17Silver c_One-C₄Alkyl or C₃-C₈Cycloalkyl], (16) -C (= NR^3-18R^3-16[Where R^3-16Is as defined above and R is^3-18Is -NR^3-3R^3-4, -OR^3-3Or NHC (O) R^3-3, In this case R^3-3And R^3-4Is as defined above], (17) CR^3-16(OR^3-19) OR^3-20[Where R^3-16Is as defined above and R is^3-19And R^3-20Are the same or different and they are C_One-C₄Alkyl or both-(CH₂)_j-18], (18) -C (NR^3-3R^3-21) (R^3-16) (R^3-9), (19) -C (OR^3-5) (R^3-16) (R^3-4), (20) -C (O-C (O) R^3-5) (R^3-16) (R^3-4), (21) -C (OR^3-5) ((CH₂)_t-NR^3-3(R^3-4) (R^3-4)), (22) -C (NR^3-3R^3-21) (R^3-16) (R^3-9) [Where R^3-3, R^3-4, R^3-9And R^3-16Is as defined above and R is^3-21Silver r^3-4Or -NR^3-4R^3-5, In this case R^3-4And R^3-5Is as defined above, wherein R is independently selected from², R³And R⁴At least one of is H.

◆ X ¹ is selected from the group consisting of NR ¹⁵ , CR ¹⁶ R ¹⁷ , S, SO, SO ₂ or O,

Wherein R ¹⁵ is (1) -H, (2) C ₃ -C ₆ alkyl, (3)-(CH ₂ ) _p -aryl, (4)-(CH ₂ ) _p -C (= 0) -R ^15-1 , (5) -C (= O) -R ^15-1 , (6) -C (= O)-(CH ₂ ) _p -C (= O) R ^15-1 , (7) SO ₂ -R ^15-3 , (8) (C = O) -Het, (9) 2-pyridyl, (10) 2-pyrimidinyl, (11) 3-pyridazinyl or (12) 2-quinolyl [ ^Wherein R ^15-1 is selected from the group consisting of —H, C ₁ -C ₆ alkyl, aryl, (CH ₂ ) _p -aryl, or (CH ₂ ) _p —OR ^15-2 , in which case R ^15-2 is selected from -H, C ₁ -C ₆ alkyl, aryl, (CH ₂ ) _p -aryl or -C (═O) -C ₁ -C ₆ alkyl, R ^15-3 is C ₁ -C ₆ alkyl, or aryl], wherein aryl is halogen, C ₁ -C ₆ alkyl, C ₁ -C ₄ alkoxy, C ₁ -C ₄ alkylthio, -OH, -NH ₂ , SH,- Phenyl unsubstituted or substituted with one or more substituents selected from the group consisting of NO ₂ or —OC (═O) —OCH ₃ , Het is a 5-membered group having one or more atoms selected from the group consisting of N, O and S , 6 won, 8 won , A 9 or 10 membered heteroaromatic moiety;

R ¹⁶ and R ¹⁷ are each independently (1) -H, (2) C ₁ -C ₆ alkyl, (3) C ₁ -C ₆ alkoxy, (4) C ₁ -C ₆ alkylthio, (5)- (CH ₂ ) _n -OR ^16-1 , (6) NR ^16-2 R ^17-2 , (7) N = CH-NR ^16-3 R ^17-3 , (8) -C (= O) -NR ^16-2 R ^17-2 , ^consisting of (9) (CH ₂ ) _n -C (= 0) -R ^16-4 and (10) (CH ₂ ) _n -Q ¹ ,-(CH ₂ ) -W ^{1 Wherein} R ^16-1 is -H, C ₁ -C ₆ alkyl,-(CH ₂ ) _n -OR ^16-5 ,-(CH ₂ ) _n -C (= 0) -R ^{16- 4} , —C (═O) — (CH ₂ ) _n —OR ^16-3 or tosyl, in which case R ^16-2 and R ^17-2 are each independently —H, C ₁ -C ₆ alkyl, — ( CH ₂ ) _n -OR ^16-5 , -C (= 0) -R ^16-4 , -C (= 0) -NR ^16-5 R ^17-5 ,-(CH ₂ ) _p -aryl and -Het R ^16-5 and R ^17-5 are each independently selected from the group consisting of —H, C ₁ -C ₆ alkyl or methoxymethyl, and R ^16-3 and R ¹⁷ Each ^-3 independently represents a group consisting of -H, C ₁ -C ₆ alkyl, -C (= 0) -R ^16-4 and (CH ₂ ) _p -aryl, wherein R ^16-4 is -H, -OH, C _Group consisting of _1- C ₆ alkyl, C ₁ -C ₆ alkoxy, -O-CH ₂ -OC (= O) -R ^{16-5 and-} (CH ₂ ) _n -C (= O) -OR ^16-5 is selected from is selected from a), Q ¹ is a 1 to 2:00 saturated 5 membered heterocyclic moiety having the atoms selected from the group consisting of N, O or S, W ¹ is the group consisting of N, O and S A 6-membered heterocyclic moiety having 1 to 2 atoms selected from;

R ¹⁶ and R ¹⁷ together are = O, = NR ^17-4 , = S, = CR ^16-3 R ^17-3 or Q ¹ , where R ^17-4 is -OR ^16-1 , C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy and — (CH ₂ ) _p -aryl.

◆ Y ¹ is hydrogen or halogen.

◆ Y _m : Y is CR ⁷ and m is 0, 1 or 2

If m is 0, there is no Y part, so there is no central ring in formula (I) (ie, the dotted line in formula (I) represents no bond),

when m is 1 Y is taken together with the third carbon of the oxazolidinone ring to form a tricyclic-conjugated 5-membered ring, R ⁷ is one or two moieties, where R ⁷ is R ^7-1 And two parts comprising R ^7-2 are each bonded to the same carbon in the tricyclic conjugated five-membered ring, which in turn is an oxazolidinone ring (ie, the dotted line of formula (I) is a single bond). Is bonded to a third carbon of R ^7-1 and R ^7-1 are each independently H, C ₁ -C ₃ alkyl, Cl, Br, OH or I, and when R ⁷ is one part, A double bond (ie, a dotted line in formula (I) is a double bond) exists between the carbon atom to which R ⁷ is attached and the third carbon of the oxazolidinone ring, or a carbon atom and an oxazolidinone ring to which R ⁷ is bonded There is a single bond between the third carbons of (that is, the dotted line of formula (I) is a single bond), R ⁷ is -C (= 0) H,

When m is 2 Y _m is CR ⁷ CR ⁸ , which together with the third carbon of the oxazolidinone ring form a tricyclic conjugated 6 membered ring, wherein R ⁷ and R ⁸ are each one or two moieties Either of which, when R ⁷ and R ⁸ are both one part, a double bond is formed between the carbon atoms including Y to which the carbon atom is bonded, and R ⁷ and R ⁸ are both H and R ⁷ and R ^When both are two parts, R ⁷ comprises R ^7-1 and R ^7-2 , wherein any one of R ^7-1 and R ^7-2 is hydrogen and the remainder is H, OH or OC (= O) R ^7-3 , wherein R ^7-3 is C ₁ -C ₃ alkyl or phenyl optionally substituted with 1 or 2 F, Cl, OH or OCH ₃ , and R ⁸ is R ^{8 -1} and R ^8-2 , wherein any one of R ^8-1 and R ^8-2 is H and the other is H, OH or OC (= 0) R ^8-3 , wherein R ^8-3 is 1 or 2 F, Cl, a C ₁ -C ₃ optionally substituted with OH or OCH ₃ Is a keel or phenyl).

Z ₁ is —O, —N, —S, —SO ₂ , SO, NR ¹⁸ , —SNR ^9-1 or S (O) NR ^9-1 ,

Wherein R ¹⁸ is —H, C ₁ -C ₆ alkyl, —C ( ^═O ) —R ^18-1 , C (═O) —OR ^18-1 and C ( ^═O ) — (CH ₂ ) _p -C (= 0) R ^18-1 , wherein R ^18-1 is H, C ₁ -C ₆ alkyl,-(CH ₂ ) _p -aryl, or-(CH ₂ ) _p- OR ^18-2 , wherein R ^18-2 is —H, C ₁ -C ₆ alkyl, or (CH ₂ ) _p -aryl,

R ^9-1 is optionally substituted with -H, (-Cl, -F, -OH, C ₁ -C ₄ alkoxy, NH ₃ , C ₁ -C ₈ alkylamine or C ₁ -C ₈ dialkylamine C ₁ -C ₄ alkyl, -p-toluenesulfonyl, C (R ⁹ R ¹⁰ ), wherein R ⁹ and R ¹⁰ are each independently —H, —C ₁ -C ₈ alkyl, —C ₁ -C ₈ alkoxy, -C ₁ -C ₈ alkylthio,-(CH ₂ ) _m -OR ⁵¹ , -O- (CH ₂ ) _m -OR ⁵¹ , NR ⁴² R ⁵² , -N = CH-NR ⁴⁴ R ⁴⁵ , -C (= 0) -NR ⁴⁴ R ⁵⁵ , -C (= 0) -NR ⁴² R ⁵² or-(CH ₂ ) _m -C (= A ¹ ) -R ^41, or they are joined together to form = 0, -NR ⁴³ , = S, CR ⁴⁴ R ⁵⁴ , or optionally substituted or unsubstituted saturated 5 or 6 membered hetero ring having 1 to 3 heteroatoms selected from the group consisting of nitrogen atom, oxygen atom, sulfur atom And R ⁴¹ is —H, — (CH ₂ ) _m —OH, C ₁ -C ₈ alkyl, C ₁ -C ₈ alkoxy, —O—CH ₂ —OC (═O) —R ¹¹ , or — (CH ₂ ) _m -C (= O) -OR ¹¹ , wherein R ¹¹ is -H, C ₁ -C ₈ alkyl, methoxymethyl, R ⁴² And R ⁵² are each independently —H, — (CH ₂ ) _m —OR ¹¹ , C ₁ -C ₈ alkyl, —C (═O) —R ⁴¹ , C (═O) —NR ¹¹ R ¹² ,-( CH ₂ ) _p -phenyl, thiazol-2-yl, or they may be joined together to form a pyrrolidino group, a piperidino group, a piperazino group, a morpholino group or a thiomorpholino group, each of which is C _May be substituted by _1- C ₄ alkyl or — (CH ₂ ) _m —OH, wherein R ¹¹ and R ¹² are each independently —H, C ₁ -C ₈ alkyl, methoxymethyl, and R ⁴³ is -H, -OR ⁵¹ , C ₁ -C ₈ alkyl, C ₁ -C ₈ alkoxy,-(CH ₂ ) _p -phenyl, -NR ⁴² R ⁵² , -NH-C (= NH) -NH ₂ , [1 , 2,4] triazol-4-yl, or cyano, and R ⁴⁴ and R ⁴⁵ are each independently —H, C ₁ -C ₈ alkyl, —C (═O) —R ⁴¹ or — (CH ₂ ) _p - are phenyl, R ⁵¹ is -H, C ₁ -C ₈ alkyl, C ₁ -C substituted with one or more _hydroxy-8 alkyl, C ₂ -C ₈ alkenyl, C ₁ -C ₈ halogenoalkyl ,-(CH ₂ ) _m -C (= O) -R ₁₁ ,-(CH ₂ ) _m -C (= O) -R ₄₁ , -C (= O)-(CH ₂ ) _m -OR ⁴⁴ Is chubby,

R ⁹ is optionally COOR ^9-2 , where R ^9-2 is -C (O) -R ^9-3 , -PO ₃ or -P (O) (OH) ₂ , in which case R ^9-3 Is C ₁ -C ₆ alkyl, —N (R ^9-4 ) ₂ , C ₁ -C ₆ alkyl-N (R ^9-4 ) ₂ , -phenyl-N (R ^9-4 ) ₂ (where R ^9-4 is -H or C ₁ -C ₆ alkyl,-(CH ₂ ) _p -R ^9-5 , where R ^9-5 is -H, -CH ₃ , CH ₂ CH ₃ , isopropyl, t -Butyl, phenyl, pyridyl, acetyl, difluoroacetyl, hydroxyacetyl, benzoyl, methoxy carbonyl, ethoxy carbonyl, 2,2,2-trifluoroethoxy carbonyl, cyanomethyl, 2 Cyanoethyl, carbomethoxymethyl, 2-carbomethoxyethyl, 2-fluoroethoxy carbonyl, benzyloxy carbonyl, t-butoxy carbonyl, methyl sulfonyl, phenyl sulfonyl or paratoluenesulfonyl -Phenyl-NHC (O) CH ₂ NH ₂ , -C ₂ H ₄ , morpholinyl, pyridinyl, C ₁ -C ₆ alkyl-OH, C ₁ -C ₆ alkyl-OCH ₃ , C _1- C ₅ alkyl, _{-C (O) CH 3, -OC} 1 -C 6 -OCH 3, (C 1 -C ₃ alkyl optionally coming from a Substituted) C ₁ -C ₃ alkyl-piperazinyl, imidazolyl, C ₁ -C ₆ alkyl, -COOH, -C (CH ₂ OH) and ₂ CH _3,

R ⁹ is optionally a 5-membered heterocyclic ring (azoiyl) of the formula C ^* H = NDBA ^* wherein the symbols or atoms representing the atoms represented by * in each formula are joined to form a ring, A, B and D Are independently oxygen, nitrogen, sulfur or carbon, in which case piperazine nitrogen is bonded to the carbon atom of the carbon-nitrogen double bond.

◆ A ¹ is an oxygen atom or ethylene ketal,

◆ i 'are each independently 0 or 1,

◆ j 'is independently 2 or 3,

◆ k 'is each independently 1 or 2,

◆ m 'is each independently 0, 1 or 2,

◆ n 'are each independently 0, 1 or 2,

◆ p 'is each independently 1, 2, 3 or 4,

Q 'is independently 3, 4 or 5,

T is independently 1, 2 or 3;

In one aspect of the invention, the oxazolidinone antibiotic is a compound of formula III:

Where

X is O, S, SO, SO ₂ , SO ₂ SNR ⁴⁰ or S (O) NR ⁴⁰ ,

◆ R ²¹ is C ₁ -C ₆ unsubstituted or substituted with one or more of hydrogen, F, Cl, hydroxy, C ₁ -C ₈ alkoxy, C ₁ -C ₈ acyloxy or —O—CH ₂ -phenyl; Alkyl, C ₁ -C ₆ cycloalkyl, amino, C ₁ -C ₈ alkylamino, C ₁ -C ₈ dialkylamino or C ₁ -C ₈ alkoxy,

◆ R ²⁴ is H, CH ₃ , CN, CO ₂ H, CO ₂ R or (CH ₂ ) _m R ⁴¹ , except that X is non-zero, and R ²⁴ is H,

◆ R ²² and R ²³ are each independently H, F or Cl,

◆ R ²⁵ is H, R ²³ is H or CH ₃ , except X is 0 and R ²⁴ is CH ₃

◆ R ⁴⁰ is independently H, C (unsubstituted or substituted with chloro, fluoro, hydroxy, C ₁ -C ₈ alkoxy, amino, C ₁ -C ₈ alkylamino or C ₁ -C ₈ dialkylamino) _1- C ₄ alkyl or p-toluenesulfonyl,

◆ R ⁴¹ is hydrogen, OH, OR ²¹ , OCOR ²¹ , NH ₂ , NHCOR ²¹ or N (R ⁴⁰ ) ₂ and m is 0, 1 or 2.

The compounds of formula (III) are described in U.S. Pat.Nos. 5,688,792 and 5,880,118, which are partially preferred due to their potency against staphylococci of complex resistance and their low minimum inhibitory concentrations. .

Oxazolidinone antibiotics and their synthesis are known in the art. Oxazolidinone antibiotics and Specific examples of synthetic schemes is to ones (U.S. Patent Nos. 5,929,248, 5,922,707, 5,880,118, 5.83787 million, 5801246, 5756732, 5736545, 5700799, 5652238, 5688792, 5668286, 5654435, 5654428, 5565571, 5.54795 million, 5.24709 million, 5,231,188, 4,977,173, 4,948,801, 4,461,773 and 4,340,606, the entire contents of each of which are incorporated herein by reference. Particularly preferred oxazolidinones are compounds of formula (IV):

It has been found that common oxazolidinone antibiotics, and especially compounds of formulas (III) and (IV), can be administered topically over the eye. Oxazolidinone antibiotics can be supplied to the ocular surface in a variety of ways, including as ophthalmic ophthalmic solutions or suspensions, as ophthalmic ointments, and ocular inserts, but the method of use is not limited thereto. Any technique for supplying oxazolidinone antibiotics to the outer surface of the eye and ocular dosage forms has the meaning of "apply topically." Although the outer surface of the eye is generally the outer layer of the conjunctival juncture, the sclera, cornea or other ocular tissue may be exposed, such as by rotation of the eye or a surgical procedure, which may become the outer surface.

The topical supply of oxazolidinone antibiotics is an amount effective to prevent or treat infection in eye tissue, which means that the infection is delayed or inhibited by the conditions of use. For target bacteria or parasites, generally at least about MIC ₅₀ is delivered to the eye tissue by an effective amount of topical use. More specifically, a concentration in eye tissue of about 0.25 μg / g or more, preferably 1 μg / g or more, more preferably about 10-50 μg / g or more is required. Generally, tissue concentrations above about 50 μg / g, in particular 100 μg / g, fall within or below the toxic response range. The amount of oxazolidinone antibiotics actively supplied to the outer surface of the eye will be much higher than the tissue concentration. This reflects the fact that the penetration of oxazolidinone antibiotics by the outer tissue layer of the eye is not only inhibited, but also the amount of antibiotics administered by the natural cleansing process is reduced, which is achieved by a weak concentration gradient. do. Therefore, when a large amount is supplied to the outside, a larger amount of antibiotic is injected into the tissue.

Oxazolidinone antibiotics can be used topically to prevent or treat various types of diseases associated with eye infections. For example, diseases of the conjunctival plexus such as blepharitis, conjunctival rotitis, mybomitis, acute or chronic erythroma, granulomas, folliculitis, lacrimitis, injectable acne, conjunctivitis, neonatal ophthalmitis and trachoma, Corneal diseases such as corneal ulcers, superficial and internal keratitis, keratoconjunctivitis, foreign bodies and postoperative infections, anterior and uveal diseases such as endophthalmitis, infectious uveitis and postoperative infections, and can be treated by topical use of oxazolidinone antibiotics The disease is part of the tissue. Infection prevention includes surgery as well as preliminary surgical treatments performed prior to other suspected infectious diseases or contacts. Examples of preventive situations include blepharoplasty, removal of chalazia, surgical procedures such as tarsorrhapy, procedures for Canualiculi and tear drainage systems, and eyelid and tear devices Surgical procedures such as other surgical procedures; Conjunctival surgery including traumatic lesions and conjunctival pieces such as ptyregia, pingueculae and tumor removal, conjunctival transplantation, amputation, burns and abrasions; Corneal surgery including removal of foreign bodies, corneal incisions and corneal transplantation; Refractive surgery, including refractive correction procedure; Glaucoma surgery involving filtration blisters; Puncture of the anterior; Iris resection; Cataract surgery; Retinal surgery; And surgery on the extraocular muscles. Preventing neonatal eye infections is also included.

More generally, oxazolidinone antibiotics can be used to treat or prevent ocular infections caused by various bacteria or parasites, which include Staphylococcus aureus and Staphylococcus epidermis. Staphylococcus, including staphylococcus epidermidis ; Streptococcus, including streptococcus pneumoniae and streptococcus pyrogenes , as well as streptococci of the C, F and G groups and the Viridian Group of streptococci ; Haemophilus influenzae (Haemophilus influenza) containing Bio-type III (H. Aegyptius); Haemophilus ducreyi ; Moraxella catarrhalis ; Neseria including Neisseria gonorrhoeae and Neisseria meningitidis ; Calamidia including Chalamydia trachomatis , Chalamydia psittaci and Chalamydia pneumoniae ; Mycobacterium including Mycobacterium tuberculosis and Mycobacterium avium -cellular complexes as well as M. pylori. Marium, M. Paul Tui gap and M. Atypical mycobacterium, including Kelone ( M. marinum, M. fortuitm and M. chelonae ); Bordetella pertussis ; Campylobacter jejuni ; Legionella pneumophila ; Bacteroides bivius ; Clostridium perfringens ; Peptostreptococcus species; Borrelia burgdorferi ; Mycoplasma pneumoniae ; Treponema pallidum ; Eureplasma urealyticum ; Toxoplasma (toxoplasma); Malaria (malaria); And one or more organisms such as nosema , but are not limited thereto.

Oxazolidinone antibiotics are used in an ophthalmically acceptable composition comprising an ophthalmically acceptable carrier and an oxazolidinone antibiotic, usually against the outer surface of the eye. The term "ophthalmically acceptable carrier" is used in a broad sense, including any substance or composition that contains and can release an oxazolidinone antibiotic that is compatible with the eye. Typically ophthalmically acceptable carriers are water or aqueous solutions or suspensions, but also oils used to prepare ointments and polymer matrices such as those used as ocular inserts. In general, oxazolidinone antibiotics are water soluble. Therefore, an aqueous solution of an oxazolidinone antibiotic can be prepared and used for topical use. Polymeric suspending agents may also be used to impart sustained release of antibiotics, and such polymeric suspending agents may possess all properties of insolubility to form a polymerizable suspension, or water soluble to form no polymerizable suspension. Oxazolidinone may be present in the form of a suspension or solution, or both. One embodiment of the present invention is an aqueous composition comprising a water-soluble polymerizable suspending agent in solution form, with oxazolinone in the form of a solution or suspension or both. As is known in the art, ointments and solid dosage forms may be used as the delivery composition.

The concentration of oxazolidinone antibiotics present in the ophthalmic composition depends on the dosage form, release rate, dosing regimen and site and form of infection. Generally speaking, the concentration for the fluid composition is about 0.01% to 5%, more typically 0.1% to 2%, and 0.05% to 50% for solid dosage forms, but the composition is not limited thereto.

Fluid ophthalmic compositions of the present invention comprising aqueous solutions, ointments and suspensions have a viscosity suitable for the chosen route of administration. Viscosities in the range of about 1,000 to 30,000 centipoise are useful for eye drops, and about 30,000 to about 100,000 centipoise are advantageous viscosity ranges for ribbon ophthalmic compositions, which can be adjusted by various methods known to those skilled in the art. .

The ophthalmic composition may contain one or more of a surfactant, an adjuvant containing additional medicine, a buffer, an antioxidant, a tonicity modifier, a preservative, a thickener, or a viscosity modifier. Preferred additives in the formulation are sodium chloride, EDTA (disodium edate), and / or BAK (benzalkonium chloride), sorbic acid, methyl paraben, propyl paraben, chlorohexidine, glycerine and sodium perborate. In a preferred embodiment, the solution may include sodium chloride, EDTA (disodium edate), and / or BAK (benzalkonium chloride), sorbic acid, chlorohexidine, glycerin and sodium perborate. In another preferred embodiment, the ointment may include methyl parabens, propyl parabens and chlorobutanol.

Another aspect of the invention relates to the use of an additional medicament for use in combination with an oxazolidinone antibiotic. Compositions comprising oxazolidinone antibiotics, additional medicaments, and ophthalmically acceptable carriers can advantageously simplify administration, while at the same time preventing or treating complex diseases or symptoms. The "additional medicament" which may be present in any of the ophthalmic composition forms described herein, including fluid and solid forms, is a pharmaceutically active compound that is efficacious for ocular use, which is an oxazolidinone antibiotic and an eye It is compatible with. Typically, additional medications include other antibiotics, antibacterial agents, antifungal agents, anesthetics, anti-inflammatory agents including steroidal and nonsteroidal anti-inflammatory agents, and anti-allergic agents. Examples of suitable medicaments include aminoglycosides such as amikacin, gentamycin, tobramycin, streptomycin, netylmycin and kanamycin; Macrolides such as azithromycin and erythromycin; Fluoroquinolones, such as ciprofloxacin, norfloxacin, opfloxacin, trobafloxacin, lomefloxacin, levofloxacin and enoxacin; Sulfonamides; Polymycin; Chloroaminophenicol; Neomycin; Paramomycin; Collistimate; Bacitracin; Vancomycin; Tetracycline; Rifampin and its derivatives ("rifampin"); Cycloserine; Beta-lactams; Cephalosporins; Amphotericin; Fluconazole; Fluchitocin; Natamycin; Myconazole; Ketoconazole; Corticosteroids; Diclofenac; Flurbiprofen; Ketorolac; Suprofen; Comoline; Rodoxamide; Levocavastin; Napazoline; Antazoline; And peniramimans. Such other medicaments, which are present in pharmaceutically effective amounts, are known to those skilled in the art. The amount for the fluid composition is generally in the range of about 0.01% to 5%, more generally 0.1% to 2%, and the amount for solid dosage forms is 0.5% to 50%.

Aqueous ophthalmic compositions (solutions or suspensions) for use in the present invention use water that contains no physiologically or ophthalmically harmful components, usually using purified or deionized water. The pH is adjusted to within the range of about 5.0 to 8.5 by the addition of an acid, base or buffer that adjusts any physiologically and ophthalmically acceptable pH. Examples of acids include acetic acid, boric acid, citric acid, lactic acid, phosphoric acid, hydrochloric acid, and examples of bases are sodium hydroxide, sodium phosphate, sodium borate, sodium citrate, sodium acetate, sodium lactate, tromethamine, THAM (trihydroxy) Methylamino-methane) and the like. Salts and buffers include citrate / dextrose, sodium bicarbonate, ammonium chloride and mixtures of these acids with bases.

The osmotic pressure ([pi]) of the aqueous ophthalmic composition is generally 10 to about 400 milliosmolar (mOsM), more preferably 260 to 340 mOsM. If desired, osmotic pressure can be adjusted by using an appropriate amount of physiologically and ophthalmically acceptable salts or excipients. It is preferred to use sodium chloride to approach the physiological fluid, the amount of sodium chloride being from about 0.01% to about 1%, more preferably from about 0.05% to 0.45% by weight based on the total weight of the composition It is common to do To obtain an osmotic pressure within the above range, equivalent amounts of cations such as potassium, ammonium, and the like, and chloride, citrate, ascorbate, borate, phosphate, bicarbonate, sulfate, thiosulfate, bisulfate, sodium One or more of anions such as bisulfate, ammonium sulfate, and the like may be used instead of or in addition to sodium chloride. Similarly, sugars such as mannitol, dextrose, sorbitol, glucose and the like can also be used to control osmotic pressure.

With a preferred form of the invention, a sufficiently high tissue concentration is achieved at a minimum dosage for use of a therapy that is simply administered to prevent or treat a bacterial or parasitic infection. Preferred techniques for this purpose include contacting the outer surface of the eye to form or supply a reservoir of oxazolidinone antibiotic. By reservoir is meant an oxazolidinone antibiotic source that is not rapidly removed by tears or other eye cleansing mechanisms. This allows high or low concentrations of oxazolidinone antibiotics to be present in the fluid on the outer surface of the eye, either alone or continuously. In general, it is believed that the absorption and penetration rates vary depending on both the dissolved drug concentration and the duration of contact between the external tissue and the fluid containing the drug. Since the drug is removed by absorption into the ocular fluid and / or eye tissue, a larger amount of drug is provided, for example, in the ophthalmic fluid supplied from the reservoir while dissolved.

The reservoir can take various forms as long as the oxazolidinone antibiotic can be provided at a sufficient concentration and the oxazolidinone antibiotic can be discharged from the reservoir, which reservoir is not easily removed from the eye. The reservoir generally remains for at least about 30 minutes, preferably at least 2 hours, more preferably at least 4 hours after administration. Herein, "remaining" means that none of the reservoir composition or oxazolidinone antibiotic is lost or removed from the ocular surface prior to the indicated time. In some embodiments, the reservoir can remain for at least 8 hours. Typical ophthalmic reservoir forms include aqueous polymerizable suspensions, ointments and solid inserts.

Ointments are known ophthalmic compositions, which are essentially oil based carriers. Generally ointments are used with lanolin bases with the addition of petroleum and / or usually from 0.1% to 2% of active ingredient and excipients. Typical bases include mineral oil, petroleum, and combinations thereof, but the oil base is not limited thereto. Ointment is usually applied as a ribbon on the lower eyelid. Discomfort when using ointments is that they are difficult to administer, and not only get on the hands, but are also uncomfortable for the patient, for example because of the frequent blurred vision.

Inserts are another known ophthalmic dosage form, which consists of a matrix containing the active ingredient. The matrix is generally a polymer and the active ingredient is generally dispersed here or bonded to the polymer matrix. This active ingredient is slowly released from the matrix through dissolution or hydrolysis such as covalent bonds. In some embodiments, the polymer is erosive (soluble), the dissolution rate of which can control the release rate of the active ingredient dispersed therein. In another form, the polymer matrix is an erosive polymer that breaks down, such as hydrolysis, by which the active ingredient bound or dispersed therein is released. The matrix and active ingredient may be surrounded by a polymeric applicator, such as a sandwich structure of matrix / matrix + active / matrix, to better control release as is known in the art. Suitable polymer types for use as matrices are well known in the art. The oxazolidinone antibiotic can be dispersed into the matrix material or can be dispersed in the monomer composition used to prepare the matrix material prior to polymerization. The amount of oxazolidinone antibiotic is generally about 0.1% to 50%, more typically about 2% to 20%. Inserts can be inserted by the patient or physician differently depending on the location and the mechanism used to hold the insert within a certain position, which is generally inserted below the upper eyelid. Various forms and arrangements are known in the art. Preferably, a biodegradable or bioerodible polymer matrix is used to ensure that spent inserts are not removed. As the biodegradable or bioerodible polymer degrades, dissolves, or erodes, the captured oxazolidinone antibiotic is released. Although it can be used alone because the insert can be released over a long period of time, it is generally difficult to insert and brings discomfort to the patient.

Aqueous polymerizable suspension forms are preferred, wherein at least one of the oxazolidinone antibiotic or the polymeric suspending agent is suspended in an aqueous medium having the above properties. It is generally possible for the oxazolidinone antibiotic to be present in suspension or in the form of both solutions and suspensions in a significant amount of at least 5% in either phase (weak concentration and relatively high total concentration to alleviate water solubility). However, oxazolidinone antibiotics are typically present in solution. Although water-soluble suspending agents are also suitable for use with suspensions of oxazolidinone antibiotics, it is preferred that the polymerizable suspending agents are suspensions (ie, water insoluble and / or water swellable). The suspending agents impart stability to the composition, increasing the residence time on the eye of the dosage form. It is also possible to enhance the sustainability of the drug in terms of obtaining longer release times and more uniform release curves.

Examples of polymerizable suspending agents include dextran, polyethylene glycol, polyvinylpyrrolidone, polysaccharide gels, gelrite®, cellulose polymers such as hydroxypropyl methylcellulose, polymers or copolymers of acrylic acid, such as In addition to carboxyl group-containing polymers, there are other polymerizable analgesics. More preferred polymerizable suspending agents are polymers which are water swellable and water insoluble, especially crosslinked carboxyl group-containing polymers.

Crosslinked carboxyl group-containing polymers substantially used in the present invention are generally known in the art. In a preferred embodiment, such polymers comprise at least about 90% by weight, based on the total weight of monomers present in one or more carboxyl group-containing monoethylenically unsaturated monomers (or sometimes referred to as carboxyl-vinyl polymers), Preferably from about 95% to about 99.9% by weight. Acrylic acid is a preferred carboxyl group-containing monoethylenically unsaturated monomer, but methacrylic acid, ethacrylic acid, β-methacrylic acid (crotonic acid), cis-α-methylcrotonic acid (angelic acid), trans-α-methylcrotonic acid ( Tiglic acid), α-butylcrotonic acid, α-phenylacrylic acid, α-benzylacrylic acid, α-cyclohexyl acrylic acid, β-phenylacrylic acid (cinnamic acid), kumaric acid (o-hydroxycinnamic acid), umbelic acid Other unsaturated polymerizable carboxyl group-containing monomers such as (p-hydroxycoumaric acid) and the like can be used in place of or in addition to acrylic acid.

Such polymers may be crosslinked with a multifunctional crosslinking agent, preferably a bifunctional crosslinking agent. The amount to be crosslinked should be sufficient to form insoluble polymer particles, but not unduly affect the sustainability of the oxazolidinone antibiotic. Typically the polymer is only crosslinked to a slight degree. Preferably the crosslinking agent is contained in an amount of about 0.01% to about 5%, preferably about 0.1% to about 5.0%, more preferably about 0.2% to about 1%, based on the total weight of monomers present do. Among such crosslinking agents, divinyl glycol; 2,3-dihydroxyhexa-1,5-diene; 2,5-dimethyl-1,5-hexadiene; Divinylbenzene; N, N-diallylacrylamide; Non-polyalkenyl polyether difunctional crosslinking monomers such as N, N-diallylmethacrylamide and the like. Also included herein are polyalkenyl polyether crosslinkers containing at least two alkenyl ether groups per molecule, preferably polyhydric alcohols containing at least 4 carbon atoms and at least 3 hydroxy groups, for example polyallyl sucrose And alkenyl ether groups containing terminal H ₂ C = C <groups prepared by etherification using alkenyl halides such as allyl bromide such as polyallyl pentaerythritol and the like. See US Patent No. 2,798,053 to Brown, which is incorporated by reference. Diisocyanate-hydroxyalkyl acrylate or methacrylate reaction products of isocyanate terminated prepolymers derived from insoluble diacrylates and polyacrylates and methacrylates, polyester diols, polyether diols or polysiloxane diols of diols and polyols Diolefinic and hydrophilic high molecular weight crosslinkers having a molecular weight of about 400 to about 8,000 can also be used as crosslinking agents, the disclosures of which are incorporated by Muller et al., The entire contents of each patent being incorporated herein by reference. See US Patent Nos. 4,192,827 and 4,136,250.

Crosslinked carboxyl-vinyl polymers can be prepared from carboxyl-vinyl monomers or monomers as monoethylenically unsaturated monomers present alone, with crosslinking agents or other agents. Methyl methacrylate, ethyl acrylate, butyl acrylate, 2-ethylhexyl acrylate, instead of about 40% or less, preferably about 0% to 20% by weight of the carboxyl group-containing monoethylenically unsaturated monomer or monomer, Physiological and ophthalmic, including acrylic and methacrylic acid esters such as octyl methacrylate, 2-hydroxyethyl-methacrylate, 3-hydroxypropylacrylate, and the like, vinyl acetate, N-vinylpyrrolidone, and the like Preferred are polymers using at least one non-carboxyl group-containing monoethylenically unsaturated monomer or monomer containing only non-toxic substituents, which are described more professionally as such additional monoethylenically unsaturated monomers. , U. S. Patent No. 4,548, 990 to Mueller et al., Which is incorporated herein by reference in its entirety. I hope that.

Particularly preferred polymers are microcrosslinked acrylic acid polymers, wherein the monomers crosslinked are 2,3-dihydroxyhexa-1,5-diene or 2,3-dimethylhexa-1,5-diene. Among the commercially available polymers, polycarbophil (Noveon AA-1) and Carbopol® are mentioned. More preferred is a carboxyl group-containing polymer system known under the product name DuraSite® containing polycarbophil, a sustained release topical ophthalmic delivery system that releases the drug at a controlled rate. Used as a composition.

The crosslinked carboxyl-vinyl polymer used to embody the present invention is characterized by the use of conventional free radical polymerization catalysts to dry particle size up to about 50 μm in equivalent sphere diameter, e.g. dry polymer particle size. Preferably from about 1 μm to 30 μm in diameter, preferably from about 3 μm to about 20 μm, the monomers are suspension or emulsion polymerized. It is preferred not to use polymer particles obtained by mechanically grinding larger polymer particles to this size. In general, the molecular weight of the polymers is reported to vary from about 250,000 to about 4,000,000, and 3,000,000,000 to 4,000,000,000.

In a more preferred embodiment of the invention, the crosslinked carboxyl-vinyl polymer particles are monodisperse, meaning that at least 80% of the particles have a particle size distribution present within a 10 μm band of the main particle size distribution. More preferably at least 90% of the particles, most preferably at least 95% of the particles are present in the 10 μm band of the main particle size distribution. In addition, the monodisperse particle size means that 20% or less, preferably 10% or less, most preferably 5% or less of the particle size is less than 1 μm. The use of monodisperse particles not only achieves maximum viscosity, but also increases the residence time in the eye of an ophthalmic drug delivery system for a given particle size. Most preferred are monodisperse particles having a particle size of 30 μm or less. If the particle size distribution is narrow, it is easy to obtain good particle packing.

The aqueous polymerizable suspension is generally 0.05% to 1.0% for oxazolidinone antibiotics, preferably 0.1% to 0.5%, more preferably 0.1% to 0.25%, and 0.1% to 10% for polymerizable suspending agents. And preferably 0.5% to 6.5%. In a more preferred embodiment, which may comprise one or more solubility enhancers, the aqueous polymerizable suspension is generally 0.05% to 5.0%, preferably 0.1% to 2.0%, more preferably 0.2 for oxazolidinone antibiotics. % To 1.50%, and 0.1% to 10%, preferably 0.5% to 6.5% for the polymerizable suspending agent. In the case of the water-insoluble and water-swellable crosslinked carboxyl-vinyl polymer, more preferred amounts of polymerizable suspending agents range from 0.5% to 2.0%, preferably from 0.5% to about 1.2% by weight of the composition. In an amount of from 0.6% to 0.9% in certain embodiments. Even if used alone, one or more polymerizable suspending agents, such as a crosslinked carboxyl group-containing polymer, may be used in an amount corresponding to the above range. In one more preferred embodiment, the composition comprises 0.5% to 1.0% of polycarbophil, such as NOVEON AA-1. More preferably 0.6% to 0.8%. In another preferred embodiment, the oxazolidinone antibiotic is a compound of formula (IV) and the suspension is 0.1% to 5.0%, preferably 0.2% to 4%, more preferably 0.3 of the compound of formula (IV) % To 3.5%, most preferably 1.0% to 2.0%.

In order to increase the solubility of oxazolidinone antibiotics, solubility enhancers may be added to the aqueous composition. Preferred solubility enhancers include polyethylene glycol, ethoxylated castor oil (trade name: Cremphor), and hydroxypropyl of α-cyclodextrin, β-cyclodextrin, γ-dextrin, hydroxyethyl, glucosyl, maltosyl and pato Cyclodextrins such as triosyl derivatives. A particularly preferred solubility enhancer is hydroxypropyl-βcyclodextrin (HPBC), which can be added to further increase the solubility of any of the aqueous compositions. In one embodiment, the composition comprises 0.1% to 20% of hydroxypropyl β-cyclodextrin, more preferably 1% to 15% of hydroxy-β-cyclodextrin, and even more preferably 2.5% to 10% Hydroxypropyl-β-cyclodextrin. The amount of solubility enhancer used depends on the amount of oxazolidinone in the composition, with more solubility enhancers being used for higher amounts of oxazolidinone.

In one embodiment, the insoluble finely crosslinked carboxyl-vinyl polymer particle amount, pH, and osmotic pressure may be correlated with each other and the degree of crosslinking is Brookfield Digital with a No. 25 spindle and a small sample adapter of 13R at 12 rpm. The viscosity of the composition measured at room temperature (about 25 ° C.) using an LVT viscometer is set to be about 500 to about 100,000 centipoise, preferably about 1,000 to about 30,000 or about 1,000 to 10,000 centipoise. In addition to this, if the viscosity is in the range of 500 to 3000 centipoise, it can be measured with the Brookfield model DV-11 +, which selects the number cp-52 spindles at 6 rpm.

When water-soluble polymers are used as suspending agents, such as hydroxypropyl methylcellulose, the viscosity will generally be from about 10 to about 400 centipoise, more typically from about 10 to about 200 centipoise or from about 10 to about 25 centipoise.

The aqueous polymerizable suspension of the present invention may be formulated so that the aqueous polymerizable suspension maintains the same or substantially the same viscosity as before it is administered to the eye in the eye. In addition, they can be formulated to better gel upon contact with tears. For example, if a formulation containing DuraSite® or other similar polyacrylic acid type polymer is administered to the eye at a pH of less than about 6.7, the formulation will have higher pH (about 7) It will swell upon contact. This gelation or more gelation causes the oxazolidinone antibiotic to be trapped, making it more difficult for the antibiotic to elute out of the composition. Eventually, all these phenomena provide a better feeling for the patient and increase the contact time of the oxazolidinone antibiotics with the eye tissue, thereby increasing the degree of drug absorption and the duration of action of the formulation in the eye.

The retention time in the eye of a viscous gel resulting from eye drops is generally in the range of about 2 hours to about 12 hours, for example about 3 hours to 6 hours. Formulations contained in such drug delivery systems may include any drug delivery aid, such as the drug itself and the physical form of the drug, the degree of drug loading, and the pH of the system, as well as ion exchange resins that are compatible with the ocular surface. It is released from the gel at a rate that depends on the factor.

The compositions used to topically deliver the oxazolidinone antibiotics of the invention can be prepared from known or readily available materials by using techniques known by those skilled in the art without undue experimentation. The oxazolidinone antibiotic can be combined with other ingredients in a dosage form selected by conventional methods known in the art.

Oxazolidinone antibiotic-containing compositions are generally used in the eyes of humans or non-human animals, where such animals include cattle, sheep, horses, pigs, sheep, rabbits, dogs, cats and other mammals. The compositions may be used as eye drops, ointments, viscous solutions or gels, ribbons or solids, and may be used topically in the front of the eye, under the upper eyelid, on the lower eyelid and in the cul-de-sac. Can be used as It can be used for the treatment of an intraocular infection or for prevention before surgery.

All percentages cited herein are in weight percent unless otherwise noted. The following examples are intended to illustrate certain features of the present invention, but are not limited thereto.

Examples 1, 3, 6, 8 and 9

Hydroxypropylmethyl cellulose, sodium chloride, sodium edate (EDTA) and surfactant were dissolved in a beaker containing about one third of the final weight of water and stirred for 10 minutes using an overhead mixer. The drug was added and stirred for 30 minutes to disperse. The solution was sterilized by applying high pressure at 121 ° C. for 20 minutes. Instead of doing so, the drug may be dried and sterilized, sterile powder may be added, or the drug may be sterilized if the drug is water soluble. Mannitol, Poloxamer 407, BAK and boric acid were individually dissolved in about half of the final weight of water, added by sterile filtration (0.22 μm filter) and stirred for 10 minutes to form a mixture. The mixture was adjusted to the desired pH with 10 N sodium hydroxide while stirring, adjusted to final weight with water by sterile filtration, and then filled into the combined dosing vessel under aseptic conditions.

Examples 2, 4, 5, 7 and 10

Neveon AA-1 was slowly dispersed into a beaker containing about one third of the final weight of water and stirred for 1.5 hours using an overhead stirrer. Neveon AA-1 is non. F. Goodrich [B.F. Goodrich] is an acrylic acid polymer commercially available. Sodium edate (EDTA), sodium chloride and surfactant were then added to the polymer solution and stirred for 10 minutes after each addition. The pH of the polymer suspension is about 3.0 to 3.5. The drug was added and stirred for 30 minutes to disperse and the mixture was sterilized by applying high pressure at 121 ° C. for 20 minutes. Instead of doing so, the drug may be dried and sterilized, sterile powder may be added, or the drug may be sterilized if the drug is water soluble. BAK, mannitol and boric acid were individually dissolved in about half of the final weight of water, added to the polymer mixture by sterile filtration (0.22 μm filter) and stirred for 10 minutes. The mixture was adjusted to the desired pH with 10 N sodium hydroxide while stirring, adjusted to final weight with water by sterile filtration, and then filled into the combined dosing vessel aseptically.

ingredient One 2 3 4 5 6 7 8 9 10 Drug 1 0.1 0.5 Drug 2 0.1 0.05 Drug 3 0.5 Drug 4 0.1 Drug 5 0.5 Drugs6 0.1 Drug7 0.1 0.5 NaCl 0.2 0.2 0.2 0.1 0.1 0.1 0.1 0.1 0.1 0.1 Mannitol 1.0 1.0 1.0 1.0 1.0 1.0 1.0 1.0 1.0 1.0 Boric acid 0.75 0.75 0.75 0.75 0.75 0.75 0.75 EDTA 0.1 0.1 0.1 0.1 0.1 0.1 0.1 0.1 0.1 0.1 HPMC 2.0 2.0 2.0 2.0 2.0 Noveon AA-1 0.8 0.8 0.8 0.8 0.8 BAK 0.01 0.01 0.01 0.01 0.01 0.01 0.01 0.01 0.01 0.01 NaOH q.s. q.s. q.s. q.s. q.s. q.s. q.s. q.s. q.s. q.s. water q.s. q.s. q.s. q.s. q.s. q.s. q.s. q.s. q.s. q.s.

Drug 1: N-((3- (fluoro-4- (4-morpholinyl) phenyl) -2-oxo-5-oxazolidinyl) methyl) acetamide (shown in formula (IV)).

Drug 2: (S) -N-((3- (3-fluoro-4-4- (1-oxothiomorpholin-4-yl) phenyl) -2-oxo-5-oxazolidinyl) methyl) Acetamide.

Drug 3: (S) -N-((3- (3-fluoro-4- (3-thiazolidinyl) phenyl) -2-oxo-5-oxazolidinyl) methyl) acetamide.

Drug 4: 3- (4-morpholinylpropionic acid, 2- (4- (4- (5-((acetylamino) methyl) -2-oxo-3-oxazolidinyl) -2-fluorophenyl)- 1-piperazinyl) 2-oxoethyl ester.

Drug 5: 8- [5- (S)-[(acetylamino) methyl] -3-oxo-3-oxazolidinyl] -1,2,4a, 5-tetrahydropyrazino [2,1-c] [1,4] benzoxazine-3 (4-H) -carboxylic acid phenylmethyl ester.

Drug 6: (S) -1- (4- (5- (acetylamino-methyl) -2-oxo-oxazolidin-3-yl) -2-fluoro-phenyl) -piperidine-4-car Acid ethyl ester.

Drug 7: (S) -N-[(3- [3-fluoro-4- [4- (2-oxazolyl) -1-piperaziayl] phenyl] -2-oxo-5-oxazolidinyl] Methyl] acetamide (1-A).

Example 11-32

Examples 11-32 are aqueous polymeric suspensions comprising an oxazolidinone compound of formula (IV). Examples 11 to 32 are prepared by the following method:

Polycarbophil (Neveon AA-1) was slowly dispersed in a beaker containing about one third of the final weight of water and stirred for 1.5 hours using an overhead stirrer. EDTA, sodium chloride and surfactant were then added to the polymer solution and stirred for 10 minutes after each addition. The pH of the polymer suspension was approximately 3.0 to 3.5. Compounds of formula (IV) were added and dispersed for 30 minutes by stirring, then the mixture was sterilized by applying high pressure at 121 ° C. for 20 minutes. Instead of doing so, the drug may be dried and sterilized, sterile powder may be added, or the drug may be sterilized if the drug is water soluble. The remaining ingredients were individually dissolved in about half of the final weight of water, added to the polymer mixture by sterile filtration (0.22 μm filter) and stirred for 10 minutes. The mixture was adjusted to the desired pH with 10 N sodium hydroxide while stirring, adjusted to final weight with water by sterile filtration, and then filled into the combined dosing vessel aseptically. The pH of each formulation was about 6, and the viscosity and osmotic pressure were about 1500 cps and about 280 mOsm / kg, respectively.

Tables 2 and 3 below show example compositions of an aqueous polymerizable suspension comprising an aqueous polymerizable suspension comprising an oxazolidinone compound of formula (IV) as well as a control that does not use a compound of formula (IV). have.

Example 12 13 14 15 16 17 18 19 20 21 22 Polycarbophil 0.75 0.75 0.75 0.75 0.75 0.75 0.75 0.75 0.75 0.75 0.75 EDTA 0.1 0.1 0.1 0.1 0.1 0.1 0.1 0.1 0.1 0.1 0.1 Sodium chloride 0.3 0.3 0.3 0.3 0.3 0.3 0.3 0.3 0.3 0.3 0.3 BAK 0.01 0.01 0.01 0.02 0.02 0.02 0.02 0.02 0.02 0.02 Chlorohexidine Gluconate - - 0.018 - - - - - - - - glycerin 0.5 0.5 0.5 0.5 0.5 0.5 0.5 0.5 0.5 0.5 0.5 Sorbitol 1.5 - - - - - - - - - - Mannitol - 1.5 1.5 1.5 1.5 1.5 1.5 1.5 1.5 1.5 1.5 HPBC - 2.5 - - - - - - 2.5 2.5 2.5 Poloxamer-407 0.1 - 0.1 - - - - - - - - Compound of formula (IV) 0.25 0.50 0.25 0.20 0.20 0.30 0.10 - 0.50 0.25 -

Example 23 24 25 26 27 28 29 30 31 32 33 Polycarbophil 0.75 0.75 0.75 0.75 0.75 0.75 0.75 0.75 0.75 0.75 0.75 EDTA 0.1 0.1 0.1 0.1 0.025 0.1 0.1 0.025 0.1 0.1 0.1 Sodium chloride 0.1 0.1 0.1 0.3 0.3 0.3 0.1 0.3 0.3 0.3 0.1 BAK 0.02 0.02 0.02 0.02 - 0.02 0.02 - 0.02 0.02 0.02 Chlorohexidine Gluconate - - - - - - - - - - - glycerin 0.5 0.5 0.5 0.5 0.5 0.5 0.5 0.5 0.5 0.5 0.5 Sorbitol - - - - - - - - - - - Mannitol 1.0 1.0 1.0 1.5 1.0 1.5 1.0 1.0 1.5 1.5 1.0 HPBC 5.0 5.0 5.0 2.5 5.0 - 5.0 5.0 - 2.5 5.0 Poloxamer-407 - - - - - - - - - - - Compound of formula (IV) 1.0 0.5 - 0.50 0.50 0.2 1.0 - - - -

The above discussion of the present invention mainly relates to preferred embodiments and experiments of the present invention. It will be readily apparent to one skilled in the art that more changes and modifications may be made in the practical application of the concepts described herein without departing from the spirit and scope of the invention as defined by the following claims.

Claims (54)

An aqueous polymerizable suspension comprising water, 0.05% to 5.0% oxazolidinone antibiotic, and 0.1% to 10% polymerizable suspending agent, A suspension comprising a crosslinked carboxyl-vinyl polymer wherein the polymerizable suspending agent is water swellable and water insoluble. The suspension of claim 1 wherein the suspension comprises 0.1% to 2.0% oxazolidinone antibiotic and 0.5% to 6.5% polymerizable suspending agent. The suspension of claim 1 wherein the polymerizable suspending agent further comprises at least 90% acrylic acid monomer and 0.1% to 5% crosslinking agent. The suspension of claim 3 wherein the crosslinker comprises a bifunctional crosslinker. The method of claim 4, wherein the crosslinking agent is divinyl glycol, 2,3-dihydroxyhexa-1,5-diene, 2,5-dimethyl-1,5-hexadiene, divinylbenzene, N, N-diallyl Suspension, characterized in that it is selected from the group consisting of acrylamide, N, N- diallyl methacrylamide and mixtures thereof. The suspension according to claim 4, wherein the crosslinking agent is selected from the group consisting of 2,3-dihydroxyhexa-1,5-diene and 2,3-dimethylhexa-1,5-diene. The suspension of claim 1 wherein the polymerizable suspending agent further comprises polycarbophil. 8. A suspension according to claim 7, wherein the suspension comprises 0.5% to 1.0% polycarbophil. The suspension of claim 1 further comprising an additional medicament. 10. The suspension according to claim 9, wherein the additional medicament is selected from the group consisting of antibiotics, antibacterial agents, antifungal agents, anesthetics, anti-inflammatory agents and anti-allergic agents. The suspension of claim 10 wherein the additional medicament is from about 0.01% to about 5.0% of the suspension. The suspension of claim 1 wherein the polymerizable suspending agent has a monodisperse particle size distribution. An aqueous polymerizable suspension comprising water, 0.05% to 5.0% oxazolidinone antibiotic, and 0.1% to 10% polymerizable suspending agent, Suspension, characterized in that the polymerizable suspension comprises polycarbophil. 14. A suspension according to claim 13, wherein the suspending agent comprises 0.1% to 2.0% oxazolidinone antibiotic and 0.5% to 6.5% polycarbophil. The suspension of claim 14 wherein the suspension comprises 0.6% to 0.8% polycarbophil. The suspension of claim 13 wherein the polymerizable suspending agent has a monodisperse particle size distribution. The suspension of claim 13 further comprising an additional medicament. 18. The suspension according to claim 17, wherein the additional medicament is selected from the group consisting of antibiotics, antibacterial agents, antifungal agents, anesthetics, anti-inflammatory agents and anti-allergic agents. The suspension of claim 18 wherein the additional medicament is from about 0.01% to about 5.0% of the suspension. The suspension of claim 13 further comprising 0.1% to 5% bifunctional crosslinking agent. The method of claim 20 wherein the crosslinker is divinyl glycol, 2,3-dihydroxyhexa-1,5-diene, 2,5-dimethyl-1,5-hexadiene, divinylbenzene, N, N-diallyl Suspension, characterized in that it is selected from the group consisting of acrylamide, N, N- diallyl methacrylamide and mixtures thereof. 21. The suspension of claim 20 wherein the crosslinker is selected from the group consisting of 2,3-dihydroxyhexa-1,5-diene and 2,3-dimethylhexa-1,5-diene. A composition comprising water, a polymerizable suspending agent and a compound of formula (IV): The composition of claim 23, wherein the composition comprises 0.1% to 5.0% of the compound of formula (IV). The composition of claim 23, wherein the composition comprises 0.2% to 4.0% of the compound of formula (IV). The composition of claim 23, further comprising a bifunctional crosslinking agent. 27. The method of claim 26, wherein the crosslinking agent is divinyl glycol, 2,3-dihydroxyhexa-1,5-diene, 2,5-dimethyl-1,5-hexadiene, divinylbenzene, N, N-diallyl A composition characterized in that it is selected from the group consisting of acrylamide, N, N- diallyl methacrylamide and mixtures thereof. 28. The composition of claim 27, wherein the crosslinker is selected from the group consisting of 2,3-dihydroxyhexa-1,5-diene and 2,3-dimethylhexa-1,5-diene. The composition of claim 23 further comprising additional medicament. 30. The composition of claim 29, wherein the additional medicament is selected from the group consisting of antibiotics, antibacterial agents, antifungal agents, anesthetics, anti-inflammatory agents and anti-allergic agents. 31. The composition of claim 30, wherein the additional medicament is from about 0.01% to about 5.0% of the composition. The composition of claim 23, wherein the polymerizable suspending agent has a monodisperse particle size distribution. The composition of claim 23 wherein the polymerizable suspending agent comprises polycarbophil. 34. The composition of claim 33, wherein the composition comprises 0.5% to 6.5% polycarbophil. 35. The composition of claim 34, wherein the composition comprises 0.6% to 0.8% polycarbophil. The composition of claim 23, wherein the polymerizable suspending agent comprises a crosslinked carboxyl-vinyl polymer that is water swellable and water insoluble. The composition of claim 23, wherein the polymerizable suspending agent comprises a cellulose polymer. 24. The composition of claim 23, wherein the polymerizable suspending agent comprises at least 90% acrylic acid monomer. A composition comprising water, oxazolidinone, a polymerizable suspending agent and a solubility enhancer. 40. The composition of claim 39, wherein the suspension comprises 0.1% to 5.0% of a compound of formula (IV) and the solubility enhancer is cyclodextrin. 41. The composition of claim 40, wherein the composition comprises 0.2% to 4.0% of a compound of formula (IV) and 0.1% to 20% of cyclodextrin, wherein the cyclodextrin is hydroxypropyl-β-cyclodextrin. . 41. The composition of claim 40, further comprising a bifunctional crosslinking agent. 43. The method of claim 42 wherein the crosslinker is divinyl glycol, 2,3-dihydroxyhexa-1,5-diene, 2,5-dimethyl-1,5-hexadiene, divinylbenzene, N, N-diallyl A composition characterized in that it is selected from the group consisting of acrylamide, N, N- diallyl methacrylamide and mixtures thereof. 44. The composition of claim 43, wherein the crosslinking agent is selected from the group consisting of 2,3-dihydroxyhexa-1,5-diene and 2,3-dimethylhexa-1,5-diene. 41. The composition of claim 40, further comprising an additional medicament. 46. The composition of claim 45, wherein the additional medicament is selected from the group consisting of antibiotics, antibacterial agents, antifungal agents, anesthetics, anti-inflammatory agents and anti-allergic agents. 47. The composition of claim 46, wherein the additional medicament is from about 0.01% to about 5.0% of the composition. 41. The composition of claim 40 wherein the polymerizable suspending agent has a monodisperse particle size distribution. 41. The composition of claim 40, wherein the polymerizable suspending agent comprises a cellulose polymer. 41. The composition of claim 40, wherein the polymerizable suspending agent comprises at least 90% acrylic acid monomer. 40. The composition of claim 39, wherein the solubility enhancer is ethoxylated castor oil. 41. The composition of claim 40, wherein the cyclodextrin is α-cyclodextrin. 41. The composition of claim 40, wherein the cyclodextrin is β-cyclodextrin. 41. The composition of claim 40, wherein the cyclodextrin is γ-cyclodextrin.